1. Field of the Invention
The invention relates to lyophilization, more particularly to improved methods and apparatus for bulk lyophilization.
2. Description of Related Art
Freeze drying, or lyophilization, is a dehydration technique. It takes place while a product is in a frozen state (ice sublimation under a vacuum) and under a vacuum (drying by gentle heating). These conditions stabilize the product, and minimize oxidation and other degradative processes. The conditions of freeze drying permit running the process at low temperatures, therefore, thermally labile products can be preserved. Freeze drying has become an accepted method of processing heat sensitive products that require long term storage at temperatures above freezing.
Steps in freeze drying include pretreatment, freezing, primary drying and secondary drying. Pretreatment includes any method of treating the product prior to freezing. This may include concentrating the product, formulation revision (i.e., addition of components to increase stability and/or improve processing), decreasing a high vapor pressure solvent or increasing the surface area. Methods of pretreatment include: freeze concentration, solution phase concentration, and formulating specifically to preserve product appearance or to provide lyoprotection for reactive products. The term "lyoprotection" refers to stabilization during all of the freeze drying process (i.e., during both freezing and drying).
The second step is to freeze the product. Freezing the product decreases chemical activity by decreasing molecular movement. Freezing is essentially the dehydration step in freeze drying; once the solvent matrix is in the solid (frozen) state, the solute matrix is "dry," (although it may contain some bound water. A rule of thumb for freezing product is that the product container should preferably not be filled with product to more than half of its total volumetric rating. In practice this may also mean filling the product only to certain depth to facilitate freezing, ice sublimation and final water/solvent removal. This helps insure, in most cases, that the surface to depth ratio is such that freeze drying is not impeded by the product depth.
How a product is frozen is determined in part by the type of product container and freeze dryer to be used. If larger flasks are to be used in conjunction with a manifold freeze dryer the product should be shell frozen. The rotation of a flask, around its vertical or tilted axis, either by hand in a dry ice alcohol bath or by using a bath specifically designed for shell freezing, increases the surface area substantially. This shell freezing technique promotes conditions of more compact development of large drying surfaces when freeze drying larger volumes of product in flasks although the formation of ice crystals may depend on false movement.
If large numbers of smaller product containers are to be processed in a tray dryer, static or plug freezing is performed. The serum bottle, vial or ampule is filled to the appropriate level and the product is frozen while the container is in an upright position. This type of freezing is typically employed with product volumes of 25 ml or less.
When a product is to be processed in a tray/shelf dryer, the product containers are loaded into trays for introduction to the freeze dryer. If the product has been prefrozen the shelves of the tray dryer should be pre-cooled to a temperature slightly below the freezing point of the product. In most cases the room temperature product is introduced to room temperature shelves of the tray/shelf dryer. The tray/shelf dryer refrigerator is then activated to freeze the product. The refrigerator may be used to reach the temperature below the eutectic and glassy state temperatures of product and solutes. Then the primary drying may begin, e.g. the sublimation of ice crystals at low pressure and at temperatures low enough to reduce cake softening and collapse. After removal of the ice crystals by sublimation, the remaining matrix may still contain bound water/solvent that may be removed by slow heating under low pressure conditions. The drying temperature may be gradually increased as the water content in the dried matrix decreases. Any local overheating of the product matrix may cause localized product deterioration and/or collapse.
When the product reaches a temperature above 0.degree. C., secondary drying may have already begun. A product in secondary drying often appears dry. However, some "bound" solvent may still remain in the apparently dry product. During secondary drying, a vacuum pump creates a low pressure condition that promotes removal of bound solvents. The amount of residual water or solvent in the lyophilized product is dependent on the length of time the product remains in secondary drying. Final level of water/solvent content is important for product storage, e.g. if the water content is too high the product matrix may experience melting and collapse if the storage temperature is increased. Uniformity of water/solvent removal across large areas and volumes of product is thus very important to protect product from local deterioration during lyophilized product storage at ambient temperatures.
Once the product is at the end of its lyophilization cycle it should be removed from the freeze dryer. In a stoppering shelf/tray dryer, an inert gas may be bled into the chamber forming an inert "gas cap" over the product prior to stoppering. Many products are simply stoppered while under vacuum. The stoppers used most commonly on serum vials/bottles have a vacuum integrity of approximately 5 years when used in conjunction with tear off seals. Once the product is stoppered, the system is returned to atmospheric pressure and the shelves are unloaded.
Bulk trays may be used in lyophilization processes to preserve products or intermediates for further processing. Bulk trays typically contain many times the volume of product or intermediate contained in a conventional lyophilization stopped vial/bottle. Therefore, if it is necessary to store a product or intermediate for further processing through lyophilization, bulk lyophilization reduces the amount of handling of the product or intermediate as compared to lyophilizing in vials. This is a significant advantage in terms of cost and contamination.
However, bulk lyophilization has some drawbacks. If bulk trays are used in the freeze drying product, the system is brought to atmospheric pressure and the trays are then unloaded. Product processed in this way likely will absorb the water vapor with which it comes in contact. Consequently this product should be processed or stored as quickly as possible. Due to exposure of the product surface to the environment there is a possibility of contamination. Therefore, bulk lyophilization (filling the open trays, loading the open trays into lyophilizer and unloading the open trays from lyophilizer, etc.) requires a clean room environment, with attendant high cost of the room, cost of its maintenance, complex operational procedures, etc. Subsequent handling of powder (e.g., emptying the open trays with elevated edges) or powder reconstitution with liquid also requires a clean room environment. Further, flat, open, shallow trays being filled and handled create the possibility of spills.
Finally, bulk lyophilization trays preferably are flat enough to match the contours of the shelf and promote good heat transfer between the shelf and the tray. This condition may not be easy to maintain during multiple uses of trays--such trays may be too flimsy and may become warped. Warpage may lead to non-uniform lyophilization--a clear disadvantage.
There is therefore a need for improved methods and apparatus for lyophilization to address the problems noted above.